Factors influencing drug absorption

Drug absorption is influenced by the biological variables of gastrointestinal tract, like transit time, pH, presence of food, secreted detergents, gut motility and the expression level of transporters and enzymes. Moreover, the net pharmacokinetic

performance of the drug is also the consequence of the drug properties determining its solubility, penetrability and affinity to transporters and enzymes.

1.2.2.1. Biological variables of the small intestine that influence drug absorption

Residence time

Gastric residence and intestinal transit time influence drug absorption. This is especially true for dissolution-limited drugs. The mean gastric residence time is shorter than that of the intestine (28). Relatively high inter-individual variability also exists.

Fed/fasted state, dosage form (tablet, capsule, solution, suspension etc.), drug particle size (an important physical parameter of the dissolution rate) and the volume of co-administered water all impact residence time.

pH

There is a pH gradient along the GI tract, which ranges from more acidic in the stomach to acidic/neutral in the small intestine. The solubility, dissolution and penetrability of ionizable drugs are sensitive to these pH variations. The pH range in the stomach and the jejunum varies greatly depending on the fasted/fed state (29).

Active transports

Drug absorption is particularly strongly influenced by both active influx and efflux transport processes for compounds with low passive penetrability. Based on gene expression levels, the most abundant active transporters in the human intestine are HPT1 (human peptide transporter 1), PEPT1 (peptide transporter 1), BCRP, MRP2, MDR1 and MCT1 (monocarboxylic acid transporter 1) (30). A compound with P-gp liability may overcome the intestinal barrier due to saturation at high intestinal dose and display a non-linear PK. The P-gp level increases distally along the segments of the small intestine, with relatively low interindividual variation (≤ 2-fold) compared to CYP3A4 (> 10-fold) (31,32).

Metabolism

Drug metabolism in the gut wall can severely reduce the drug level available for absorption. CYP3A4 is a major metabolic enzyme in the intestine (33). In the upper intestinal segments, it is assumed that there is interplay between P-gp and metabolic enzymes. P-gp and 3A4 have overlapping substrate specificity and so they act in concert: P-gp reduces intracellular drug levels, therefore CYP3A4 can act more effectively at lower substrate level.

Some drugs show varying solubility and stability in different regions of the intestine as a result of changes in environmental pH, degradation by enzymes present in the lumen of the intestine or interaction with endogenous solubilising agents such as bile. In other instances active efflux or uptake transport mechanisms will modify drug absorption to various extent in certain regions of the GI tract. Such drugs display region-specific absorption i.e. they can only be absorbed efficiently in specific segments of the GI tract that are named "absorption windows" (34).

1.2.2.2. Drug properties influencing absorption

Solubility and permeability are two major features of a drug that determine its oral absorption. The Biopharmaceutical Classification System has categorized drugs in terms of their solubility and intestinal permeability. Class I compounds are defined as those with high solubility and high permeability, and predicted to be well absorbed when given orally. All other compounds (classes II-IV) suffer either from low solubility, low permeability or both, and will present challenges to the development of products with acceptable oral bioavailability (34).

Penetration of xenobiotics is a virtually continuous process of traversing hydrophilic and lipophilic phases, so the lipophilic and hydrophilic features of drugs are important in this process. The Lipinski Rule defines the likelihood of poor absorption in humans, using the structural properties of over 2000 compounds that survived Phase I clinical trials (35). The „Rule-of-Five‟ predicts that poor absorption or permeation is more likely when the number of hydrogen bond donors is more than 5, there are at least 10 hydrogen bond acceptors, the molecular weight is greater than 500 and the calculated

Log P is greater than 5. The „Rule-of-Five‟ should be considered as a qualitative predictor of absorption and permeability. With large molecular size, solubility and passive penetrability decreases. If the number of hydrogen bonds and thus the drug‟s polar feature increases, aqueous solubility will increase, but passive penetration (partitioning in the lipid bilayer of the cell membrane) will decrease. Lipophilicity above a certain level limits molecular penetration, as drugs are simply trapped in the cell membranes. For optimal absorption, a good balance of permeability and aqueous solubility is deemed in the range of 0 < logP < 3 or 1 logD_7.4 3.

Veber et al. has defined additional critical properties that are required in order to achieve good oral bioavailability in rats (36). They reported the findings from a study of rat bioavailability data for 1100 drug candidates. They found that molecules possessing fewer than 10 rotatable bonds and having a polar surface area less than 140 Ų (or H-bond count less than 12) generally showed oral bioavailability in rats exceeding 20%.

Ionizability is also a critical drug property that influences drug absorption.

Charged molecules display higher solubility than their neutral forms, yet they show lower rates of penetration. As there is a pH gradient along the gastrointestinal tract, the solubility and penetration of chargeable drugs may differ accordingly. Most drugs (75%) are weak bases, therefore less ionized and penetrate faster in the more basic segments of the GI, preferably in the small intestine.

High lipophilicity and therefore low aqueous solubility of new chemical entities is a common problem in recent drug research.